Rearrangements of the KMT2A gene are characteristic of infantile acute lymphoblastic leukemia (ALL) and are associated with increased lineage plasticity and resistance to therapy. Here, we describe the case of a 9-month-old infant with infantile ALL who experienced multiple immunophenotypic switches in her leukemia throughout therapy and ultimately achieved remission with the combination of CPX-351 and Inotuzumab. This case highlights the unique clinical challenges infantile ALL poses on monitoring therapeutic response with current methods of measuring minimal residual disease as well as the challenges in treating infantile B-ALL.

Background: While most research has largely focused on medical risks associated with reduced quality of life (QOL) in survivors, sociodemographic and family factors may also play a role. Thus, we examined sociodemographic factors and family factors associated with survivor QOL, including adolescent’s cancer-specific stress, mother’s general stress, and mother–adolescent communication. Methods: Mothers ( N=80) and survivors (ages 10-23, N=50) were assessed 5 years following initial diagnosis. Mothers completed measures regarding sociodemographic background adolescent’s cancer-specific stress, mother’s general stress, mother–adolescent communication, and adolescent QOL. Survivors also reported on their own QOL. Two hierarchical multiple regressions examined predictors of: (a) mother’s report of adolescent QOL and (b) survivor’s self-report of QOL. Results: The final model predicting mother-reported adolescent QOL was significant, F(5,74)=21.18, p<.001, and explained 59% of the variance in QOL. Significant predictors included adolescent stress ( β=-0.37, p<.001), mothers’ stress ( β=-0.42, p<.001), and communication ( β=0.19, p=.03). The final model predicting survivor-reported QOL was also significant, F(5,44)=5.16, p<.01 and explained 24% of the variance in QOL. Significant predictors included adolescent stress ( β=-.37, p=.01) and communication ( β=-.31, p=.04). Sociodemographic factors were not a significant predictor of QOL in any model. Conclusion: Family stress and communication offer potential points of intervention to improve QOL of pediatric cancer survivors from mother and survivor perspectives. While additional research is needed, healthcare professionals should encourage stress management and strong mother–child communication to enhance survivors’ long-term QOL. Such interventions may be helpful, irrespective of known sociodemographic factors that often affect health.

A document by Paul Meyers. Click on the document to view its contents.

Introduction: The risk of relapse in retinoblastoma is currently determined by the presence of high-risk histopathologic factors in the enucleated eye. However, the probability of developing metastatic disease is heterogeneous among these patients. Evaluating a biological marker to identify high-risk patients could be useful in clinical setting. This study aims to evaluate whether the expression of TFF1, a surrogate for subtype 2 retinoblastoma, is a prognostic marker for relapse and death. Methods: This multicenter cohort study included 273 patients, 48 of whom had extraocular disease. Immunohistochemical staining were performed for CRX, ARR3, TFF1 and Ki67. Tumors were classified as histological subtype 1 (HS1) if they had low or no expression of TFF1 (quick score (QS) ≤ 50) and as histological subtype 2 (HS2) if they expressed TFF1 diffusely (QS > 50). We studied the association between HS classification and outcome. Results: Of 273 patients, 35.9% were classified as HS1, 59.3% as HS2 and 4.8% were not evaluable. In multivariate analysis, patients with HS2 tumors had a higher probability of relapse and death than those with HS1 ( P < 0.0001 and P = 0.00020, respectively). We identified a higher-risk subgroup among HS2 tumors, presenting non-mutually exclusive expression of ARR3 and TFF1 and had an increased risk of relapse and death compared to tumors that displayed mutually exclusive expression ( P = 0.012 and P = 0.027, respectively). Conclusions: Expression of TFF1, especially when it is not-mutually exclusive with ARR3, is an independent prognostic marker of poor outcome in retinoblastoma.

Standard management of pediatric Non-Hodgkin’s Lymphoma (NHL) patients have included an initial assessment of the disease at presentation to establish it’s extent. This “staging” process has historically assigned patients using traditional classifications which were established decades ago when, like other pediatric malignancies, the more extensive involvement of the cancer for a patient directly correlated with the patient’s long term survival[[1]](#ref-0001). Advances in radiologic technology have evolved in the way the disease extent was evaluated, moving from conventional radiographs, to computerized tomography (CT) to magnetic resonance imaging (MRI) to most recently positron emission tomography (PET)[[2]](#ref-0002). Despite the development and use of PET scans for decades for various cancer diagnoses, the role of PET scans for NHL remains unclear[[3]](#ref-0003). Indeed, its value for many conditions is its ability to assess the response to initial therapy and establish the patient’s risk stratification guiding the remaining treatment plan[[4]](#ref-0004). Such efforts have not occurred in clinical trials of NHL and thus we are left to examine case series and try to discern its value for this disease.

Purpose Phase 1 study assessing the safety and toxicity of cabozantinib in combination with topotecan and cyclophosphamide for relapsed osteosarcoma and Ewing sarcoma. Methods Oral cabozantinib (25mg/m 2) was administered daily for 21 (dose level 1) or 14 (dose level -1B) days. Topotecan (0.75mg/m 2) and cyclophosphamide (250mg/m 2) were administered IV on days 1-5. A modified 3+3 design based upon first cycle dose-limiting toxicities (DLT) was used for dose escalation. Results Twelve patients with a median age of 15 (12.9-33.2) years were enrolled (7 with Ewing sarcoma; 5 with osteosarcoma); all were evaluable for toxicity. At dose level 1, three of six patients developed first cycle DLT: grade 3 epistaxis; grade 3 transaminitis; prolonged grade 2 thrombocytopenia. Six patients were enrolled on dose level -1B (interrupted cabozantinib, given days 8-21), with one first cycle DLT (grade 3 pneumothorax) observed. Of the 10 response evaluable patients, one had partial response (Ewing sarcoma), seven had stable disease, and two had progressive disease. Conclusions The recommended phase 2 doses and schedules for this combination are topotecan 0.75mg/m 2 IV days 1-5, cyclophosphamide 250mg/m 2 IV days 1-5, and cabozantinib 25mg/m 2 days 8-21. Non-concomitant administration of cabozantinib with cytotoxic therapy in this population has acceptable toxicity while allowing for potential disease control.

PARANEOPLASTIC JUVENILE IDIOPATHIC ARTHRITIS AS A MANIFESTATION OF A BENIGN TERATOMA IN A FIVE-YEAR-OLD GIRL

LETTER TO THE EDITORTITLE: Sarcoid-like reaction in a child following prolonged therapeutic exposure to dabrafenib and trametinib for BRAF V600E mutated hypothalamic/ chiasmatic gliomaAuthors : Mari Wilhelmsson MD, PhD1,2; Foo Jen Chun MD1; Rae S M Yeung MD, PhD3; Fiona Krtizinger MBChB, MMed4; Tata McKeown, MSc1; Ailish Coblentz, MD5; Birgit Ertl-Wagner, MD5; Uri Tabori MD, PhD1, Ute Bartels MD, PhD 1; Anirban Das MBBS, MD, DM 1AFFILIATIONS: 1. Division of Haematology Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; 2. Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden. 3. Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada. 4. Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 5. Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Ontario, Canada.WORD COUNT:   853FIGURES:  1RUNNING TITLE: Sarcoid-like reaction with BRAF/MEK-inhibitionKEYWORDS : MEK-inhibitor, BRAF inhibitor, sarcoidosis/sarcoid‑like reaction (S/SLR), Low-grade glioma, pediatric

Background: Anaplastic large cell lymphoma (ALCL) is an uncommon form of Non-Hodgkin Lymphoma (NHL) in younger patients, accounting for less than 15% of cases. The median age at presentation is 12 years and is exceedingly rare in infants. Various prognostic factors, risk stratification and novel treatment strategies have been studied in pediatric ALCL. There is no separate data available on the disease biology, treatment regimens and prognostic factors among infantile ALCL. Outcomes for infants with ALCL have been reported to be inferior to that of older children. The long-term Event Free Survival (EFS) in general among pediatric patients is approximately 70% regardless of the treatment approach. We report a case of an 8month old infant diagnosed with ALK positive ALCL with visceral organ involvement stratified as high risk and treated according to ALCL 99 protocol with excellent clinical response, on regular follow up and is disease free since 2years.

The value of reporting on end-of-treatment outcome of patients in low-income settingsTrijn Israels MD PhD1,2, Ramandeep Singh Arora DCH, MD3, Lillian Sung MD PhD41 Collaborative African Network for Childhood Cancer Care and Research (CANCaRe Africa), 2 Kamuzu University of Health Sciences, Blantyre, Malawi, 3 Max Super Speciality Hospital, New Delhi, India, 4 Sick Children’s Hospital, Toronto, CanadaCorresponding author:Dr Trijn Israels, CANCaRe Africa, Department of Paediatrics, Kamuzu University of Health Sciences (KuHES), Blantyre, Malawi. Email: [email protected] count: 1256 wordsNumber of Tables: 0Number of Figures: 0Short running title: End-of-treatment outcome reportingKey words: childhood cancer, survival, LIC, indicatorsLIC Low-income countryHIC High-income countryGICC Global Initiative for Childhood CancerEFS Event-free survivalOS Overall survivalTRM Treatment related mortalityDRM Disease related mortalityCANCaRe Africa Collaborative African Network for Childhood Cancer Care and Research

Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying systemic therapy, recognizing and treating the central nervous system as a sanctuary site, and implementing modern risk stratification to deliver varying intensities of therapy based on age, presenting white blood count (WBC), sentinel somatic genetics, and therapy response. Recently, numerous Children’s Oncology Group trials have demonstrated the lack of benefit of intensifying traditional chemotherapy, providing evidence that new approaches are needed to cure the patients for whom cure has been elusive. Distinguishing those who require intensive or novel therapeutic approaches from others who will be cured with minimal therapy is key for future trials. Incorporating new genomic biomarkers and more sensitive measures of minimal/measurable residual disease (MRD) provide opportunities to achieve these goals.

Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children’s Oncology Group cellular therapy-based trials for advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T cell depletion is used and the depth of remission as measured by next-generation sequencing based minimal residual disease assessment pre-transplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.

The Children’s Oncology Group (COG) Rare Tumor committee includes the Infrequent Tumor and Retinoblastoma subcommittees, encompassing a wide range of extracranial solid tumors that don’t fall within another COG disease committee. Current therapeutic trial development focuses on nasopharyngeal carcinoma, adrenocortical carcinoma, pleuropulmonary blastoma, colorectal carcinoma, melanoma, and thyroid carcinoma. Given the rarity of these tumors, novel strategies and international collaborative efforts are necessary to advance research and improve outcomes.

Cost effectiveness of support with out-of-pockets costs to prevent treatment abandonment in Malawi and sub-Saharan Africa; lessons learnt and the way forward – a report from CANCaRe Africa Junious Sichali1, Avi Denburg2, Harriet Khofi3, Cecilia Mdoka1, Deborah Nyirenda4, Yamikani Chimalizeni3, George Chagaluka3, Elizabeth Molyneux3, Marc Y. R. Henrion4,5, Sumit Gupta2, Trijn Israels11 Collaborative African Network for Childhood Cancer Care and Research (CANCaRe Africa), 2Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Canada,3 Kamuzu University of Health Sciences (KUHeS), Blantyre, Malawi, 4 Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi, 5Liverpool School of Tropical Medicine, Liverpool, UKCorresponding author:Dr Trijn Israels, CANCaRe Africa, Department of Paediatrics, Kamuzu University of Health Sciences (KuHES), Blantyre, Malawi. Email: [email protected] count: 1189 wordsNumber of Tables: 0Number of Figures: 0Short running title: Cost-effectiveness of treatment abandonment preventionKey words: childhood cancer, treatment abandonment, cost-effectiveness,LMIC Low- and middle-income countryGICC Global Initiative for Childhood CancerCANCaRe Africa Collaborative African Network for Childhood Cancer Care and ResearchALL Acute lymphoblastic leukaemiaGDP Gross Domestic ProductDALY Disability Adjusted Life Year

Children’s Oncology Group’s 2023 Blueprint For ResearchDouglas S. Hawkins,1 Lia Gore2Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WADepartment of Pediatrics, University of Colorado School of Medicine and Center for Cancer and Blood Disorders, Children’s Hospital Colorado,, Aurora, CO

As survival rates for childhood cancer have improved, there has been increasing focus on identifying and addressing adverse impacts of cancer and its treatment on children and their families during treatment and into survivorship. The Behavioral Science Committee (BSC) of the Children’s Oncology Group (COG), comprised of psychologists, neuropsychologists, social workers, nurses, physicians, and clinical research associates, aims to improve the lives of children with cancer and their families through research and dissemination of empirically supported knowledge. Key achievements of the BSC include enhanced interprofessional collaboration through integration of liaisons into other key committees within COG, successful measurement of critical neurocognitive outcomes through standardized neurocognitive assessment strategies, contributions to evidence-based guidelines, and optimization of patient-reported outcome measurement. The collection of neurocognitive and behavioral data continues to be an essential function of the BSC, in the context of therapeutic trials that are modifying treatments to maximize event-free survival, minimize adverse outcomes, and optimize quality of life. In addition, through hypothesis-driven research and multi-disciplinary collaborations, the BSC will also begin to prioritize initiatives to expand the systematic collection of predictive factors (e.g., social determinants of health) and psychosocial outcomes, with overarching goals of addressing health inequities in cancer care and outcomes, and promoting evidence-based interventions to improve outcomes for all children, adolescents, and young adults with cancer.

Background/Objectives: High-risk Hodgkin lymphoma (HRHL) in children is a curable with combined modality therapy. The AHOPCA is a consortium of cancer centers from Central America. In 2004, AHOPCA implemented a guideline with a short course of chemotherapy (mStanfordV), strict diagnostics and radiation guidelines, aimed at reducing abandonment and improving outcomes. Methods: Newly diagnosed children less than 18 years of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA centers were staged with chest X-ray, and ultrasound or CT. Therapy was a modified StanfordV (mStanfordV) substituting cyclophosphamide for mechlorethamine and involved field radiation. Results: Of 219 patients with HRHL, 181 patients were eligible and evaluable;146 (81%) were boys, 22% being less than 6 years; 43 were stage IIB, 84 IIIB and 54 IV. Thirty-one (17%) abandoned therapy, 28 (15%) progressed, 30 (17%) relapsed and 8 (4%) died of toxicity. Radiation guidelines were not followed. Five-year abandonment-sensitive event-free survival and overall survival (AS-EFS, AS-OS±SE) for the cohort were 46±4% and 56±4%; 5-year AS-OS for stages IIB, IIIB and IV was 76±7%, 59±7%, and 35±7% (p=0.0006). Conclusion: Despite instituting a short treatment guideline, it did not improve the abandonment rate (17%) and did not achieve the reported outcomes of StanfordV. The cyclophosphamide dose used to replace merchlorethamine was inadequate. Despite strict guidelines, the radiation therapy application was inaccuarate. Weekly chemotherapy may have adversely affected abandonment of therapy by increasing the burden of travel-time. Based on these results, AHOPCA established a new abandonment strategy and a new guideline.

Unexpected Gifts from a Cruel Monster: Caring for Children with DIPGMegan R. Schaefer, PhD1-21Department of Pediatric Psychology, Nationwide Children’s Hospital2Department of Clinical Pediatrics, The Ohio State University*Correspondence to:Megan Schaefer, PhD; Department of Pediatric Psychology, Nationwide Children’s Hospital; Columbus, OH; 700 Children’s Drive Columbus OH, 43205; Email: [email protected] word count: 1, 199Brief running title: Caring for Children with DIPGKey words: brain tumors, gliomas, pediatric palliative care, end of life careTables: 0Figures: 0Abbreviations: DIPG (diffuse intrinsic pontine glioma)Dear Diffuse Intrinsic Pontine Glioma (DIPG),You are a terrible and cruel disease. You are rare and aggressive, developing in a critical part of a child’s brain, often limiting the ability to biopsy, resect, or treat. You cheat children of the life they deserve. Because of you, the world loses out on future firefighters, scientists, teachers, and presidents. Hearing about your existence is unimaginable to a parent as you limit a child’s life expectancy to less than a year on average. Given your aggressive nature, children gradually lose parts of themselves, bit by bit. Weakness, difficulties breathing, confusion, unable to swallow, loss of speech. You trap children in their bodies, and they report feeling as if their body is an unrecognizable, foreign object. You wreak havoc on family’s lives as they try to comprehend the news that their sweet child will not live to graduate high school, become an engineer, get married, have children, and likely not play their next baseball game.The grief starts from the moment families hear your crushing acronym. Parents immediately begin to question their identity and how they will navigate life without their child. Will they be able to parent their other children? Who are they if not a parent to this special child? It becomes impossible not to imagine burying their child and planning their funeral. Siblings feel as if they lost their playmate at diagnosis and also their caregivers as they watch them slowly cocoon in a shell, enveloped with immense grief. Life becomes a ticking time bomb, and the pressure to make every birthday and holiday celebration perfect becomes crippling.You tear the hearts of pediatric neuro-oncologists around the world as they enter the room to be the bearer of excruciatingly painful news. You make families and healthcare providers feel helpless as no treatment has yet been found to fight against your awfulness. Your existence is unfair. You have turned the worlds of families upside down such that the order of the world no longer makes any sense and families feel they are constantly living in a nightmare. You are equivalent to the “D word” in invoking fear and panic, as of right now, you are a death sentence. But, I would like to remind you, you have not won, and you will not win. Despite how powerful and almighty you feel you are, our patients, families, and pediatric neuro-oncology community are stronger.As a pediatric psychologist who specializes in seeing children with brain tumors, I have walked alongside many children and families impacted by you. Despite the immense physical and emotional pain you have imposed on children and families, I have truly witnessed unexpected beautiful gifts along these journeys. While I could continue on sharing how much I hate your existence, I want to thank you for the beautiful, yet unexpected, gifts you have provided. You have taught us that joy, beauty, and love can co-exist with fear, distress, and grief. As you significantly limit life expectancy, you teach us to cherish every little moment and to find joy in the small things. You have shown us what is truly important in life, time with family and friends and following our dreams. You have reminded me to hug my loved ones a little tighter and to take the trip, chase the experience as responsibilities can always wait. You have shown us how to weather the storm and taught us about a level of faith and strength many of us never knew existed. You have strengthened our motivation and persistence to show up every day at our jobs and give 110% effort to finding a cure because no child or family ever deserves to hear the heart-wrenching news that their child has you.Many times, I have left the hospital after a day supporting children and families affected by you and felt defeated, helpless, and angry. As a helper, I want to alleviate children and families of the emotional pain and worries they are carrying. Caring for children and families impacted by you often leads to secondary trauma. It is bravely walking into situations day in and day out, expressing vulnerability and opening yourself to love on a child who we know will not survive because of you. And each clinic visit, we watch the patient’s functioning slowly fade away, and as this happens, we witness the heartache of families as they desperately seek options to prolong time together while prioritizing their child’s quality of life. Even though the child loses their ability to communicate or move their arms to give a hug, I find comfort in still seeing the sparkle in their eye, the small smirk, the head nod, the blink; the love is always there. It may be expressed differently but the room remains filled with love. Although you are pervasive and hard to ignore, I do not give my attention or memory to all the changes and losses you unfairly force on children. I remember the bell ringing after radiation, the Make-A-Wish pictures and videos, the winks, the celebration of small moments where smiles and laughter were shared through the tears. You have made us all cry more times than we would like to share, but you have also made us smile because life is messy and hard, but it is also beautiful. My heart is heavy, but it is not just filled with grief. In between the dark and torn spaces, there is love and appreciation for the children who have selflessly given me unexpected gifts through their tumultuous journey with you, and for that, I will forever be thankful. If I did not let down my walls and love on these children, I may save myself from heartache, but it would come at the cost of not getting to witness the lives of extraordinary children, so the grief is worth every ounce of pain.With a 0% cure rate, you may think you are winning this battle, but we will not give in. We will continue fighting the good fight until no child, parent, and sibling ever has to hear the devastating news that shatters their heart in a million pieces that their child is diagnosed with you. We will rise up to the challenge because the world is a much better place with our children growing up to achieve their wildest dreams. To everyone in the neuro-oncology community, thank you for your courage, persistence, and dedication to destroy DIPG. One day, we will prevail. I hope it is in my lifetime, but if not, I will continue to express my gratitude to the patients, families, and colleagues who have touched my heart and inspired me to face insurmountable obstacles with humility and grace. D iffuse I ntrinsic P ontineG lioma or D etermination, I nspiration,P assion, G ratitude. The first is you, the terrible monster who has placed heavy emotional burdens on my heart. The second is the gifts I have received from you. Not all cruel things are pure evil. There is goodness in the hard. So as I grieve the lives of change-makers whose time was cut way too short, I will find gratitude for the unexpected gifts.From a grieving yet grateful and hopeful pediatric psychologist, Dr. Megan